Experimental autoimmune encephalomyelitis (EAE) is a T cell-mediated autoimmune disease of the CNS. Metformin is the most widely used drug for diabetes and mediates its action via activating AMP-activated protein kinase (AMPK). We provide evidence that metformin attenuates the induction of EAE by restricting the infiltration of mononuclear cells into the CNS, down-regulating the expression of proinflammatory cytokines (IFN-γ, TNF-α, IL-6, IL-17, and inducible NO synthase (iNOS)), cell adhesion molecules, matrix metalloproteinase 9, and chemokine (RANTES). Furthermore, the AMPK activity and lipids alterations (total phospholipids and in free fatty acids) were restored by metformin treatment in the CNS of treated EAE animals, suggesting the possible involvement of AMPK. Metformin activated AMPK in macrophages and thereby inhibited biosynthesis of phospholipids as well as neutral lipids and also down-regulated the expression of endotoxin (LPS)-induced proinflammatory cytokines and their mediators (iNOS and cyclooxygenase 2). It also attenuated IFN-γ and IL-17-induced iNOS and cyclooxygenase 2 expression in RAW267.4 cells, further supporting its anti-inflammatory property. Metformin inhibited T cell-mediated immune responses including Ag-specific recall responses and production of Th1 or Th17 cytokines, while it induced the generation of IL-10 in spleen cells of treated EAE animals. Altogether these findings reveal that metformin may have a possible therapeutic value for the treatment of multiple sclerosis and other inflammatory diseases.

Metformin is the most widely prescribed oral anti‐diabetic and hypoglycemic drug. Here we examined the efficacy of metformin in relapsing/remitting (SJL) and chronic (C57BL/6) models of EAE. Administration of metformin restricted the infiltration of mononuclear cells in central nervous system (CNS), thereby; downregulated the expression of proinflammatory cytokines (IFN‐gamma, TNF‐alpha, IL‐6, IL‐17 and iNOS), CAMs, MMP9 and chemokine (Rantes) in CNS of treated animals. Metformin treatment restored the lipids alterations (total phospholipids and in free fatty acid) in CNS during EAE suggest a possible involvement of AMP‐activated protein kinase (AMPK) which acts as cellular energy sensor in cells. Activation of AMPK with metformin was observed in macrophages and inhibits phospholipids and neutral lipid biosynthesis. Further it down regulated the expression of pro‐inflammatory mediators (iNOS and Cox2) induced with LPS/IFN‐gamma. It also downregulated recall responses, Th1 as well as Th17 cytokines and induced IL‐10 production in total spleen cells of treated and untreated EAE animals. Together, these findings reveal that metformin may have possible therapeutic value for the treatment of multiple sclerosis and other inflammatory diseases. Grants: RG 3810‐A‐1, PP1283 from National Multiple Sclerosis Society (SG) and NS‐22576, NS‐34741, NS‐37766 and NS‐40810 from NIH (IS).

AMP-activated protein kinase (AMPK) is an energy sensing metabolic switch in mammalian cells.

IntroductionComorbidity between ED and depression is high. Causal relation between two is bidirectional. Person with ED can have MDD because of psychological factors. MDD symptoms and associated hypogonadism affect on libido and erectile function. Diseases like ankolysing spondolysis, asthma, rheumatoid arthritis, coronary heart disease, psoriasis, diabetes, and multiple sclerosis have strong co morbid ED and MDD. Inflammation is common overlapping factor in these illnesses.MethodAn internet search was made on pubmed, and psychiatrist.com, using key words, major depression, endothelial dysfunction, inflammation, erectile dysfunction, and cytokines. This was followed by study of relevant martial in different journal and books.ResultMen with ED had high levels of depressive, somatic, and anxious symptoms. Approximately one-third of people with MDD had higher levels of peripheral inflammatory marker. Incidences of ED are two fold higher in depressed people as compared with nondepressed.DiscussionLevels of pro inflammatory cytokine like IL-1,I patient L-6,TNF,CRP, interferon-gamma and homosystien are raised in MDD. Cytokines effect on the HPA axis, glucocorticoid resistance, neurotransmission and hippocampal neurogenesis. Patients treated with interferon have higher risk of developing MDD .Antidepressant therapy results in decreased inflammatory response.Erectile function depends on integrity of endothelium which is target of inflammation. Endothelial dysfunction is linked to ED as they share a common pathway through the release of nitric oxide. Proinflammatory cytokines and homosystien play role, both in ED and MDD.ConclusionInflammation and its markers need to be considered in cases of co morbid ED and MDD.